A mechanistic model of two-phase pressure drop has been developed for microchannel flow. The primary flow regimes observed in microchannel two-phase flow regime maps were the inertial dominated regime (annular flow) and the surface tension dominated regime (slug or bubbly flow). Mechanistic models of pressure drop for each of these regimes are developed and compared to pressure drop in microchannel flows of four different refrigerants with widely varying fluid properties: R134, R410A, R290 (propane) and R717 (ammonia) of varying hydraulic diameters between 70 microns to 305 microns. The mechanistic model compares favourably to the experimental pressure drop data from microchannel flow measurements with an overall mean deviation of 18.1%. The model is also compared with refrigerant-oil flow of R134a and two different weights of POE oil, using fluid property correlations developed for those mixtures, with a mean deviation of 18.9%. While this accuracy is not stellar, the significance is that no empirical coefficients were needed to close the model.